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Molecular Pharmacology

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Research ArticleArticle

Human CYP2C8 Is Post-Transcriptionally Regulated by MicroRNAs 103 and 107 in Human Liver

Shu-Yun Zhang, Sailesh Surapureddi, Sherry Coulter, Stephen S. Ferguson and Joyce A. Goldstein
Molecular Pharmacology September 2012, 82 (3) 529-540; DOI: https://doi.org/10.1124/mol.112.078386
Shu-Yun Zhang
Human Metabolism Section, Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina (S.-Y.Z., S.S., S.C., J.A.G.); and CellzDirect/Invitrogen Corp., Durham, North Carolina (S.S.F.)
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Sailesh Surapureddi
Human Metabolism Section, Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina (S.-Y.Z., S.S., S.C., J.A.G.); and CellzDirect/Invitrogen Corp., Durham, North Carolina (S.S.F.)
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Sherry Coulter
Human Metabolism Section, Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina (S.-Y.Z., S.S., S.C., J.A.G.); and CellzDirect/Invitrogen Corp., Durham, North Carolina (S.S.F.)
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Stephen S. Ferguson
Human Metabolism Section, Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina (S.-Y.Z., S.S., S.C., J.A.G.); and CellzDirect/Invitrogen Corp., Durham, North Carolina (S.S.F.)
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Joyce A. Goldstein
Human Metabolism Section, Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina (S.-Y.Z., S.S., S.C., J.A.G.); and CellzDirect/Invitrogen Corp., Durham, North Carolina (S.S.F.)
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Abstract

The CYP2C genes are extensively regulated at the transcriptional stage. The present study shows for the first time that CYP2Cs are also regulated post-transcriptionally by microRNAs (miRNAs). By using online search engines, we found potential miRNA response elements (MREs) in the 3′-untranslated region (3′-UTR) of the CYP2C mRNAs. Among these were a MRE for the miRNAs miR-103 and miR-107 in the 3′-UTR of human CYP2C8. CYP2C8 protein levels (measured through immunoblot analyses) did not correlate with CYP2C8 mRNA levels (measured through quantitative polymerase chain reaction analyses) in human liver samples. The translation efficiency (protein/mRNA ratio) for CYP2C8 was inversely correlated with the expression of miR-103 and miR-107. When three copies of the putative MRE from CYP2C8 were inserted downstream from a luciferase expression reporter, transfection with precursors for miR-103 or miR-107 decreased luciferase activity in primary hepatocytes, whereas transfection with antisense oligonucleotides (AsOs) for miR-103/miR-107 increased luciferase activity. As expected, there was no effect of the precursors or AsOs when three copies of the putative MRE were inserted in the reverse orientation. When precursors for miR-103/miR-107 were transfected into primary human hepatocytes, CYP2C8 protein levels were decreased, whereas AsOs increased CYP2C8 protein levels. Neither precursors nor AsOs affected CYP2C8 mRNA levels, which indicated that the effect was post-transcriptional. Putative MRE motifs were also found in the 3′-UTRs of CYP2C9 and CYP2C19, which suggested that the same miRNAs could regulate translation of other members of the CYP2C family, although to a lesser degree than CYP2C8. These results clearly show that CYP2Cs are regulated post-transcriptionally by miR-103 and miR-107.

Footnotes

  • This work was supported by the Intramural Research Program of the National Institutes of Health National Institute of Environmental Health Sciences [Project Z01-ES02124].

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    http://dx.doi.org/10.1124/mol.112.078386.

  • ABBREVIATIONS:

    CAR
    constitutively activated receptor
    miRNA
    microRNA
    GAPDH
    glyceraldehyde-3-phosphate dehydrogenase
    MRE
    microRNA response element
    AsO
    locked nucleic acid-modified antisense oligonucleotide
    UTR
    untranslated region
    HNF4α
    hepatocyte nuclear factor 4α
    PXR
    pregnane X receptor
    GR
    glucocorticoid receptor
    bp
    base pair(s)
    PCR
    polymerase chain reaction.

  • Received February 21, 2012.
  • Accepted June 20, 2012.
  • U.S. Government work not protected by U.S. copyright
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Molecular Pharmacology: 82 (3)
Molecular Pharmacology
Vol. 82, Issue 3
1 Sep 2012
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Research ArticleArticle

miR-103 and miR-107 Regulate Human CYP2C8 Expression

Shu-Yun Zhang, Sailesh Surapureddi, Sherry Coulter, Stephen S. Ferguson and Joyce A. Goldstein
Molecular Pharmacology September 1, 2012, 82 (3) 529-540; DOI: https://doi.org/10.1124/mol.112.078386

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Research ArticleArticle

miR-103 and miR-107 Regulate Human CYP2C8 Expression

Shu-Yun Zhang, Sailesh Surapureddi, Sherry Coulter, Stephen S. Ferguson and Joyce A. Goldstein
Molecular Pharmacology September 1, 2012, 82 (3) 529-540; DOI: https://doi.org/10.1124/mol.112.078386
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